ABCA4 and ROM1: Implications for Modification of the PRPH2-Associated Macular Dystrophy Phenotype

Abstract

Purpose: : To identify the causative mutation leading to autosomal dominant macular dystrophy, cone dystrophy and cone-rod dystrophy in a five-generation family and to explain the high intrafamilial phenotypic variation by identifying possible modifier genes.

Methods: : We investigated 15 family members by detailed ophthalmic and electrophysiologic phenotyping. Furthermore, chip-based mutation screening was performed. Patients’ genomic DNA was analyzed by sequencing analysis of PRPH2, ABCA4 and ROM1.

Results: : Heterozygous mutations were identified in three genes and showed five different combinations within the studied family. All clearly affected family members carried the heterozygous PRPH2 mutation p.R172W. Patients with heterozygous sequence alterations only in ROM1 (p.R229H) or ABCA4 (p.V2050L) showed a mild ocular phenotype and were otherwise asymptomatic. The phenotypic severity of patients carrying the PRPH2 mutation increased with additional mutations in ABCA4 or ROM1. Patients carrying all three mutations were the most severely affected.

Conclusions: : Features of a PRPH2-associated phenotype might be modulated by additional mutations in other genes (in this family ABCA4 and/or ROM1) accounting for intrafamilial variability and resulting in a cumulative effect worsening the phenotype. We suggest that families showing a variable macular dystrophy phenotype caused by mutations in PRPH2 are tested for additional mutations in ABCA4 and ROM1 as they might alter the progression of the PRPH2 phenotype implying different needs for genetic counseling.

Keywords: retinal degenerations: hereditary • genetics • electrophysiology: clinical